Journal
ONCOTARGET
Volume 5, Issue 9, Pages 2714-2722Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1931
Keywords
Lyn; N-end rule; ubiquitination; protein degradation; UBR
Categories
Funding
- Canadian Breast Cancer Foundation (CBCF)
Ask authors/readers for more resources
The activation of apoptotic pathways results in the caspase cleavage of the Lyn tyrosine kinase to generate the N-terminal truncated Lyn Delta N. This Lyn Delta N fragment has been demonstrated to exert negative feedback on imatinib induced apoptosis in chronic myelogenous leukemia (CML) K562 cells. Our investigations focus on Lyn Delta N stability and how reduced stability reduces imatinib resistance. As the proteolytical generated Lyn Delta N has a leucine as an N-terminal amino acid, we hypothesized that Lyn Delta N would be degraded by the N-end rule pathway. We demonstrated that Lyn Delta N is unstable and that its stability is dependent on the identity of its N-terminus. Additionally we established that Lyn Delta N degradation could be inhibited by either inhibiting the proteasome or knocking down the UBR1 and UBR2 ubiquitin E3 ligases. Importantly, we also demonstrate that Lyn Delta N degradation by the N-end rule counters the imatinib resistance of K562 cells provided by Lyn Delta N expression. Together our data suggest a possible mechanism for the N-end rule pathway having a link to imatinib resistance in CML. With Lyn Delta N being an N-end rule substrate, it provides the first example that this pathway can also provide a pro-apoptotic function as previous reports have currently only demonstrated anti-apoptotic roles for the N-end rule pathway.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available